A revolution in fundamental knowledge about the molecular basis of human cancer has occurred in the last fifteen years. One major challenge for the future is to apply this ever-expanding knowledge to the management of patients. Most efforts in this regard have been devoted to therapeutic strategies, and exciting advances have occasionally been made, such as those recently reported for breast cancer1 and CML2. Much less work has been devoted to diagnostic applications, even though early detection through enhanced diagnosis is widely believed to be a very effective strategy to reduce cancer mortality. Deaths from cervical cancers, for example, have decreased dramatically since the advent of routine Pap smears despite the fact that treatment for cervical cancers has not improved dramatically.
Several established strategies for the early detection of colorectal tumors have been devised. Colonoscopy, sigmoidoscopy, and barium enemas provide highly specific and sensitive tests for neoplasia3-6, but are invasive and are limited by available expertise and patient compliance7, 8. Testing for occult blood in the stool (FOB) has in some studies been shown to reduce incidence, morbidity and mortality from colorectal cancer9-13. These FOB tests are non-invasive and extremely useful, but are not completely sensitive or specific for neoplasia14-17. Furthermore, some FOB tests require patients to change their dietary habits prior to testing or require multiple tests, potentially reducing compliance7, 18, 19. There is thus a pressing need to develop new diagnostic tests that overcome these obstacles.
One of the most promising classes of new diagnostic markers comprises mutations in oncogenes and tumor suppressor genes20. As these mutations are directly responsible for neoplastic growth, they have clear conceptual advantages over indirect markers for neoplasia such as fecal occult blood. Furthermore, because these mutations only occur in a clonal fashion in neoplastic cells, they theoretically have very high specificity. Several groups have reported that mutations in cancer-related genes can be detected in the stool of colorectal cancer patients21-35. However, the sensitivities and specificities achieved have been limited either by technical impediments or low frequencies of detectable mutations in any specific gene. To increase sensitivity, investigators have recently combined tests for mutations in several different genes or combined tests for genetic alterations with other DNA-based tests that are independent of mutation32-34. There is a continuing need in the art for diagnostic methods for detection of early stages of cancer and other diseases.